B-cell non-Hodgkin's lymphoma (NHL) is the sixth most common cause of cancer-related deaths in the United States and the incidence of this disease is increasing. While aggressive lymphomas may be cured with cytotoxic therapy, most indolent lymphomas are incurable with current therapy. Novel effective therapies are therefore needed to treat these patients. We are investigating a biological combination therapy for patients with indolent lymphoma that incorporates an anti-CD20 monoclonal antibody, Rituximab, and Interleukin-12. Rituximab is a genetically engineered chimeric murine/human monoclonal antibody that binds specifically to CD20 on pre-B and mature B- lymphocytes. While binding of the Fab domain may induce apoptosis, the Fc domain recruits immune effector functions to mediate lysis of the B-cell. Interleukin-12 (IL-12) has been shown to facilitate cytolytic T-cell responses; promote the development of Th1-type helper T-cells; enhance the lytic activity of NK cells; and induce the secretion of interferon- gamma by both T and NK cells. Therefore, we hypothesized that combining IL-12 with Rituximab would augment the immune mediated cell lysis induced by Rituximab. We have shown in a recently completed Phase I trial of this combination that the optimal immunological dose of IL-12 to give with standard doses of Rituximab is 300ng/kg. A substantial increase in the serum levels of downstream molecules such as interferon-gamma and Inducible Protein-10 (IP-10) was seen in response to this dose of IL-12. We also observed a 69 percent response rate to this therapy, with many of the responses seen in heavily pretreated patients. In this application, we are proposing to further evaluate the efficacy and toxicity of the combination of IL-12 and Rituximab through two different treatment regimens in patients with indolent B-cell non-Hodgkin's lymphoma and to determine if either one is promising enough to explore further in a phase III setting. We plan to do a randomized Phase II study to evaluate the efficacy of IL-12 and Rituximab given concurrently, as in the Phase I study, and to also evaluate the efficacy of Rituximab alone with IL-12 given only if there is a suboptimal response to Rituximab or disease progression. As shown in the Phase I trial, IL-12 induces the expression of cytokines such as gamma-interferon and chemokines such as IP-10. These molecules have been shown to upregulate T-cell function and inhibit angiogenesis. A further goal of the study is therefore to evaluate, in correlative studies, whether the combination of IL-12 plus Rituximab can alter gene expression in the malignant B-cells, restore the potentially deficient T-cell repertoire and inhibit angiogenesis leading to an improve clinical outcome for patients with indolent lymphoma.